Innate immune recognition of the protozoan parasite Toxoplasma gondii has been extensively studied in the mouse, its natural intermediate host. In contrast little is known about how human innate cells, which do not express the major murine sensors TLR11 and TLR12, respond to the parasite. We have characterized the cytokine/chemokine response elicited in human peripheral blood myeloid cells upon exposure to T. gondii tachyzoites and identifying the responding cell populations. We found that proinflammatory cytokines (e.g. TNF and p40 IL-12) and chemokines are secreted by CD16+ (patrolling) but not CD16low (classical) monocytes and by CD1C, but not CD141, dendritic cells. In 2016, we have focused on understanding the basis for the differential responsiveness among monocyte subsets. We showed that the T. gondii-induced cytokine response in monocytes was accompanied by increased glycolysis and, importantly, was abolished when glycolysis is inhibited. Moreover, this type of metabolic reprograming was also observed when human monocytes were selectively stimulated by phagocytosis of live tachyzoites. The examination of a basal level of metabolism in monocyte subsets revealed that responding CD16+ and non-responding CD16low monocytes display low and high level of glycolysis, respectively. The latter findings suggest that the ability to increase the rate of glycolysis is one of factors contributing to the cytokine response of primary human CD16+ monocytes stimulated with T. gondii. Microarray data comparing T. gondii stimulated purified human monocyte subsets further support the distinct metabolic potentials of these cell populations. Although in T.gondii infected mice CD8 alpha + dendritic cells have been characterized as the principal source of IL-12, our studies with human monocytes prompted us to test whether murine monocytes may also be major producers of this or other cytokine /chemokines following stimulation with the parasite. Interestingly while purified monocytes on a cell per cell basis produced much less IL-12 than CD8 alpha+ dendritic cells, they secreted copious amounts of CXCL10, a chemokine known to play a critical role in immunity against T. gondii infection by mobilizing and inducing the accumulation of CXC3R+ effector NK and T cells. These findings suggest that in contrast to the situation in humans where responding monocytes and DC display overlapping cytokine secretion profiles,in the mouse these myeloid cell populations carry out distinct functions in host resistance to T. gondii infection. Control of most intracellular pathogens depends on production of interferon (IFN)-gamma. In mice infected with T. gondii, NK cells are a rapidly induced but temporary innate source of the cytokine prior to the activation of antigen specific IFN-gamma secreting CD4+ and CD8+ T lymphocytes. Nevertheless, recent studies on NK cells have revealed that certain sub-populations may share some of the properties of adaptive T lymphocytes such as the ability to mount memory responses. This prompted us to ask the reverse question of whether there may be an NK-like population of CD4+ T cells that could serve as a potential source of an early IFN-gamma. Indeed, Takeshi Kawabe in collaboration with Ron Germains group was able to identify in uninfected mice a population of conventional CD4+ T cells with memory (CD44+ CD62) phenotype that expresses high levels of IL-12R and T-bet and are poised to secrete IFN-gamma, properties previously attributed only to NK cells. Furthermore, his experiments indicate that these cells are able to mediate partial protection against T. gondii infection in the absence of any additional source of IFN-gamma. The NOD receptors are cytoplasmic pattern recognition receptors that recognize bacterial cell wall peptidoglycans. Unexpectedly, when infected i.p. with T. gondii, NOD1, but not NOD2 deficient mice display rapid mortality. The uncontrolled parasitemia in NOD1-/- mice was a consequence of defective adaptive rather then innate immunity and was accompanied by a systemic decrease in the number of lymphocytes. We showed that he latter phenomenon was due to impaired generation of hematopoietic lymphoid precursors and specifically to a defect in IL-7R signaling. RNA-Seq and protein comparative analyses revealed that NOD1-/- mice express a truncated form of NOD1 that lacks the CARD signaling domain, but expresses the N-terminal ligand binding portion plus the NOD domain and, thus, could serve as a dominant negative inhibitor of IL-7 receptor signalling. In 2016, employing CRISPR/Cas9 technique we targeted and deleted the truncated NOD1 form in NOD1-/- mice in order to test this hypothesis. We have now obtained viable pups and are currently expanding several colonies with distinct NOD1 truncations.